Walker Michael P, Rajendra T K, Saieva Luciano, Fuentes Jennifer L, Pellizzoni Livio, Matera A Gregory
Department of Genetics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4955, USA.
Hum Mol Genet. 2008 Nov 1;17(21):3399-410. doi: 10.1093/hmg/ddn234. Epub 2008 Aug 8.
Spinal muscular atrophy (SMA) is a recessive neuromuscular disease caused by mutations in the human survival motor neuron 1 (SMN1) gene. The human SMN protein is part of a large macromolecular complex involved in the biogenesis of small ribonucleoproteins. Previously, we showed that SMN is a sarcomeric protein in flies and mice. In this report, we show that the entire mouse Smn complex localizes to the sarcomeric Z-disc. Smn colocalizes with alpha-actinin, a Z-disc marker protein, in both skeletal and cardiac myofibrils. Furthermore, this localization is both calcium- and calpain-dependent. Calpains are known to release proteins from various regions of the sarcomere as a part of the normal functioning of the muscle; however, this removal can be either direct or indirect. Using mammalian cell lysates, purified native SMN complexes, as well as recombinant SMN protein, we show that SMN is a direct target of calpain cleavage. Finally, myofibers from a mouse model of severe SMA, but not controls, display morphological defects that are consistent with a Z-disc deficiency. These results support the view that the SMN complex performs a muscle-specific function at the Z-discs.
脊髓性肌萎缩症（SMA）是一种由人类生存运动神经元1（SMN1）基因突变引起的隐性神经肌肉疾病。人类SMN蛋白是参与小核糖核蛋白生物合成的大型大分子复合物的一部分。此前，我们发现SMN在果蝇和小鼠中是一种肌节蛋白。在本报告中，我们表明整个小鼠Smn复合物定位于肌节Z盘。在骨骼肌和心肌肌原纤维中，Smn与Z盘标记蛋白α-辅肌动蛋白共定位。此外，这种定位依赖于钙和钙蛋白酶。已知钙蛋白酶作为肌肉正常功能的一部分，可从肌节的各个区域释放蛋白质；然而，这种去除可以是直接的，也可以是间接的。使用哺乳动物细胞裂解物、纯化的天然Smn复合物以及重组SMN蛋白，我们表明SMN是钙蛋白酶切割的直接靶点。最后，严重SMA小鼠模型的肌纤维而非对照肌纤维表现出与Z盘缺陷一致的形态学缺陷。这些结果支持了Smn复合物在Z盘处执行肌肉特异性功能的观点。
